US20140163013A1 - Prophylactic or therapeutic agent for neuropathic pain associated with guillain-barre syndrome - Google Patents

Prophylactic or therapeutic agent for neuropathic pain associated with guillain-barre syndrome Download PDF

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US20140163013A1
US20140163013A1 US14/119,223 US201214119223A US2014163013A1 US 20140163013 A1 US20140163013 A1 US 20140163013A1 US 201214119223 A US201214119223 A US 201214119223A US 2014163013 A1 US2014163013 A1 US 2014163013A1
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alkyl group
hydrogen
halogen atoms
acceptable salt
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Toshiyasu Imai
Toru Kawasaki
Toru Ogawa
Kazuhide Inoue
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Kyushu University NUC
Nippon Chemiphar Co Ltd
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Kyushu University NUC
Nippon Chemiphar Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
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    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome.
  • GBS Guillain-Barré syndrome
  • GBS has been considered to be a demyelinating polyneuropathy, which attacks peripheral nervous myelin. It has recently been recognized that an axonopathy type results in a primary axonopathy.
  • GBS is a monophasic disease, and its typical symptom is weakened limb muscles. Sensory disorders including dysesthesia often occur, and nearly 90% of patients complain of pains such as nerve root pain, muscle pain, joint pain or the like. GBS may cause cranial neuropathies such as facial paralysis, ocular motor paralysis, and swallowing or articulation disorders. At the climax phase, GBS may cause such a respiratory muscle paralysis that the patient should use a respirator, and it may also cause a severe autonomic neuropathy including hypertension, hypotension, fluctuations in blood pressure, tachycardia, or bradycardia.
  • GBS Guillain-Barré syndrome
  • GBS is an autoimmune disease, and its relation with each of cellular immunity and humoral immunity has been suggested in reports. It is thought that the infectious disease prior to the crisis of GBS plays an important role.
  • GBS is a monophasic disease, and its typical symptom is weakened limb muscles. Sensory disorders including dysesthesia often occur, and nearly 90% of patients complain of pains such as nerve root pain, muscle pain, joint pain or the like.
  • GBS may cause such a respiratory muscle paralysis that the patient should use a respirator, and its case may be a severe autonomic neuropathy including hypertension, hypotension, fluctuations in blood pressure, tachycardia, or bradycardia. Therefore, a systemic management is very important at an acute phase. While recovery starts after an acute phase, pain may continue from the acute phase to a recovery phase. At the recovery phase, the pain is an obstacle to rehabilitation. Steroids, carbamazepine, opioid, gabapentin or the like have been used for the pain in a supportive care. However, the obtained analgesic effect is often insufficient.
  • paroxetine a diazepinedione derivative or the like having a P2X 4 receptor antagonism can be used as an agent for preventing or treating neuropathic pain
  • Patent documents 1 and 2 filed patent applications
  • P2X 4 receptor antagonist such as paroxetine, a diazepinedione derivative or the like can be used as an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome, and completed the present invention.
  • the present invention relates to an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome containing P2X 4 receptor antagonist as an active ingredient.
  • the invention also relates to an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome containing a compound having the following formula (I) or a pharmacologically acceptable salt thereof as an active ingredient:
  • R 1 is a halogen atom
  • R 2 is hydrogen, a halogen atom, nitro, cyano, —C(O)—OR 3 , —C(O)—NR 4 R 5 , —SO 2 —OR 3 , or —SO 2 —NR 4 R 5 , wherein each of R 3 , R 4 , and R 5 is hydrogen or a C 1-6 alkyl group; or in the alternative
  • R 1 is hydrogen
  • R 2 is a halogen atom, nitro, cyano, —C(O)—OR 3 , —C(O)—NR 4 R 5 , —SO 2 —OR 3 , or —SO 2 —NR 4 R 5 , wherein each of R 3 , R 4 , and R 5 is hydrogen or a C 1-6 alkyl group.
  • the invention further relates to an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome containing a compound having the following formula (Ia) or a pharmacologically acceptable salt thereof as an active ingredient:
  • R 1 is chloro or bromo
  • R 2 is hydrogen, chloro, bromo, nitro, or cyano; or in the alternative
  • R 1 is hydrogen
  • R 2 is chloro, bromo, nitro, or cyano.
  • the invention further relates to an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome containing a compound having the following formula (II) or a pharmacologically acceptable salt thereof as an active ingredient:
  • R is a C 1-4 alkyl group, a C 2-4 alkynyl group, phenyl (optionally having one or more substituents selected from the group consisting of a lower alkyl group, an alkylthio group, an alkoxy group, a halogen atom, nitro, an acylamino group, methylsulfonyl, and methylenedioxy), or tetrahydronaphthyl;
  • R 1 is hydrogen
  • X is hydrogen, a C 1-4 alkyl group, a trifluoroalkyl group, hydroxyl, a halogen atom, methylthio, or an arylalkoxy group.
  • the invention further relates to an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome containing a selective serotonin reuptake inhibitor as an active ingredient.
  • the invention further relates to an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome containing an agent selected from the group consisting of imipramine, nortriptyline, amitriptyline, desipramine, doxepin, fluoxetine, fluvoxamine, citalopram, and a pharmacologically acceptable salt thereof as an active ingredient.
  • an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome containing an agent selected from the group consisting of imipramine, nortriptyline, amitriptyline, desipramine, doxepin, fluoxetine, fluvoxamine, citalopram, and a pharmacologically acceptable salt thereof as an active ingredient.
  • the invention further relates to an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome containing a compound having the following formula (III) or a pharmacologically acceptable salt thereof as an active ingredient:
  • X is S or CH 2 ;
  • Y is O, S, or NH
  • R 1 is hydrogen, a C 1-8 alkyl group, a C 1-8 alkyl group having one or more halogen atoms, an aralkyl group comprising a C 1-6 alkyl moiety and a C 6-10 aryl moiety, a C 2-8 alkenyl group, carboxymethyl, or an alkoxycarbonylmethyl group comprising a C 1-8 alkoxy moiety;
  • each of R 2 and R 3 independently is hydrogen, a C 1-8 alkyl group, a C 1-8 alkoxy group, a C 1-8 alkyl group having one or more halogen atoms, a C 1-8 alkoxy group having one or more halogen atoms, a halogen atom, amino, carboxyl, hydroxyl, nitro, cyano, a C 2-8 acyl group, a C 6-10 aryl group, or a five-membered or six-membered heterocyclic group;
  • each of R 4 and R 5 independently is hydrogen, a C 1-8 alkyl group, or a C 1-8 alkyl group having one or more halogen atoms;
  • the double line consisting of a broken line and a solid line is a single bond or a double bond.
  • the invention further relates to an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome containing a compound having the following formula (IV) or a pharmacologically acceptable salt thereof as an active ingredient:
  • X a is O, S, or NH
  • R 1a is hydroxyl, tetrazolyl, N(R 5a ) (R 6a ), a C 2-8 alkenyl group, a C 2-8 alkynyl group, a C 1-8 alkyl group having one or more halogen atoms, a C 1-8 alkoxy group having one or more halogen atoms, or a C 6-10 aryl group, wherein R 5a is hydrogen or a C 1-8 alkyl group, and R 6a is hydrogen, a C 1-8 alkyl group, or a C 2-8 acyl group;
  • each of R 2a and R 3a independently is hydrogen, a C 1-8 alkyl group, or a C 1-8 alkyl group having one or more halogen atoms;
  • R 4a is hydrogen, a C 1-8 alkyl group, a C 1-8 alkoxy group, a C 1-8 alkyl group having one or more halogen atoms, a halogen atom, hydroxyl, nitro, amino, carboxyl, tetrazolyl, cyano, a C 6-10 aryl group, or a five-membered or six-membered heterocyclic group.
  • the invention further relates to an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome containing a compound having the following formula (IVa) or a pharmacologically acceptable salt thereof as an active ingredient:
  • X b is O, S, or NH
  • R 1b is a halogen atom, hydroxyl, tetrazolyl, N(R 5b )(R 6b ), a C 2-8 alkenyl group, a C 2-8 alkynyl group, a C 1-8 alkyl group having one or more halogen atoms, a C 1-8 alkoxy group having one or more halogen atoms, or a C 6-10 aryl group, wherein R 5b is hydrogen or a C 1-8 alkyl group, and R 6b is hydrogen, a C 1-8 alkyl group, or a C 2-8 acyl group;
  • each of R 2b and R 3b independently is hydrogen, a C 1-8 alkyl group, or a C 1-8 alkyl group having one or more halogen atoms;
  • R 4b is hydrogen, a C 1-8 alkyl group, an alkoxy group, a C 1-8 alkyl group having one or more halogen atoms, a halogen atom, hydroxyl, nitro, amino, carboxyl, tetrazolyl, cyano, a C 6-10 aryl group, or a five-membered or six-membered heterocyclic group; and
  • R 7b is a C 1-8 alkyl group.
  • the invention further relates to an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome containing a compound having the following formula (IVb) or a pharmacologically acceptable salt thereof as an active ingredient:
  • X c is O, S, or NH
  • R 1c is hydrogen, a halogen atom, a C 1-8 alkyl group, a C 1-8 alkoxy group, hydroxyl, tetrazolyl, N(R 5c )(R 6c ), a C 2-8 alkenyl group, a C 2-8 alkynyl group, a C 1-8 alkyl group having one or more halogen atoms, a C 1-8 alkoxy group having one or more halogen atoms, or a C 6-10 aryl group, wherein R 5c is hydrogen or a C 1-8 alkyl group, and R 6c is hydrogen, a C 1-8 alkyl group, or a C 2-8 acyl group;
  • each of R 2c and R 3c independently is hydrogen, a C 1-8 alkyl group, or a C 1-8 alkyl group having one or more halogen atoms;
  • R 4c is hydrogen, a C 1-8 alkyl group, an alkoxy group, a C 1-8 alkyl group having one or more halogen atoms, a halogen atom, hydroxyl, nitro, amino, carboxyl, tetrazolyl, cyano, a C 6-10 aryl group, or a five-membered or six-membered heterocyclic group;
  • R 7c is hydrogen or a C 1-8 alkyl group
  • R 8c is hydrogen, a C 1-8 alkyl group, or a C 2-8 acyl group.
  • the invention further relates to an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome containing a compound having the following formula (V) or a pharmacologically acceptable salt thereof as an active ingredient:
  • X is O, S, or NH
  • Y is N or NR 6 , wherein R 6 is hydrogen or a C 1-8 alkyl group
  • R 1 is hydrogen, a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 1-8 alkyl group having one to three halogen atoms, or an alkyl group having phenyl;
  • R 2 is a C 1-8 alkyl group, a C 1-8 alkoxy group, a C 1-8 alkyl group having one to three halogen atoms, hydroxyl, nitro, amino, carboxyl, tetrazolyl, or cyano;
  • R 3 is hydrogen, a C 1-8 alkyl group, a C 1-8 alkoxy group, a C 1-8 alkyl group having one to three halogen atoms, a halogen atom, hydroxyl, nitro, amino, carboxyl, tetrazolyl, or cyano;
  • each of R 4 and R 5 independently is hydrogen, a C 1-8 alkyl group, or a C 1-8 alkyl group having one to three halogen atoms;
  • n 1 or 2;
  • the double line consisting of a solid line and a broken line is a double bond
  • the double line consisting of a solid line and a broken line is a single bond.
  • the invention further relates to an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome containing a compound having the following formula (Va) or a pharmacologically acceptable salt thereof as an active ingredient:
  • R 11 is hydrogen or a C 1-8 alkyl group
  • R 21 is a C 1-8 alkyl group, a C 1-8 alkoxy group, a C 1-8 alkyl group having one to three halogen atoms, or hydroxyl;
  • R 31 is hydrogen or a halogen atom.
  • the invention further relates to an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome containing a compound having the following formula (VI) or a pharmacologically acceptable salt thereof as an active ingredient:
  • A is an aryl group optionally having one or more substituents or a heterocyclic group optionally having one or more substituents;
  • B is an aryl group optionally having one or more substituents or a heterocyclic group optionally having one or more substituents;
  • X is a C 1-5 alkylene group or a bond
  • Y is a C 1-5 alkylene group optionally comprising a double bond
  • Z is O, S, N(R 5 ), or a bond, wherein R 5 is hydrogen or a C 1-8 alkyl group;
  • each of R 1 , R 2 , and R 3 independently is hydrogen, a C 1-8 alkyl group, or a C 1-8 alkyl group having one to three halogen atoms;
  • R 4 is hydrogen, a C 1-8 alkyl group, a C 1-8 alkyl group having one to three halogen atoms, a three-membered to seven-membered cycloalkyl group, or a C 1-8 alkyl group having a three-membered to seven-membered cycloalkyl group;
  • each of n and m independently is 1 or 2;
  • the substituent of the aryl group represented by A is not an alkyl group when X is a bond.
  • the invention further relates to an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome containing a compound having the following formula (VIa) or a pharmacologically acceptable salt thereof as an active ingredient:
  • a 1 is phenyl or thienyl, each of which optionally has one to three substituents selected from the group consisting of a halogen atom, a C 1-8 alkyl group having one to three halogen atoms, nitro, cyano, hydroxyl, amino, a C 1-8 alkylamino group, a C 2-26 dialkylamino group, a C 2-8 acylamino group, a C 1-8 alkoxy group, a C 1-8 alkoxy group having one to three halogen atoms, an aryl group, and a heterocyclic group;
  • B 1 is an aryl group optionally having one or more substituents or a heterocyclic group optionally having one or more substituents;
  • Y 1 is a C 1-5 alkylene chain optionally comprising a double bond
  • Z 1 is O, S, N(R 7 ), or a bond, wherein R 7 is hydrogen or a C 1-8 alkyl group;
  • R 6 is hydrogen, a C 1-8 alkyl group, a C 1-8 alkyl group having one to three halogen atoms, or a three-membered to seven-membered cycloalkyl group.
  • the invention further relates to an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome containing a compound having the following formula (VIb) or a pharmacologically acceptable salt thereof as an active ingredient:
  • a 2 is phenyl or thienyl, each of which optionally has one to three substituents selected from the group consisting of a halogen atom, a C 1-8 alkyl group having one to three halogen atoms, nitro, cyano, acetylamino, a C 1-8 alkoxy group, a C 1-8 alkoxy group having one to three halogen atoms, an aryl group, and a heterocyclic group;
  • B 2 is phenyl, naphthyl, benzofuranyl, 1,3-benzo[d]dioxolyl, quinolyl, indolyl, benzothienyl, thienyl, or pyridyl, each of which optionally has one to three substituents selected from the group consisting of a halogen atom, a C 1-8 alkyl group, a C 1-8 alkyl group having one to three halogen atoms, nitro, cyano, hydroxyl, amino, a C 2-8 acylamino group, a C 1-8 alkoxy group, a C 1-8 alkoxy group having one to three halogen atoms, a C 6-12 aryloxy group, sulfamoyl, a C 1-8 alkylsulfamoyl group, and a C 2-16 dialkylsulfamoyl group;
  • Z 2 is O, S, or NH
  • R 8 is hydrogen or a C 1-8 alkyl group.
  • the invention further relates to an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome containing a compound having the following formula (VII) or a pharmacologically acceptable salt thereof as an active ingredient:
  • B is an aryl group optionally having one or more substituents or a heterocyclic group optionally having one or more substituents;
  • Y is a C 1-5 alkylene group optionally comprising a double bond
  • Z is O, S, N(R 5 ), or a bond, wherein R 5 is hydrogen or a C 1-8 alkyl group;
  • each of R 1 , R 2 , and R 3 independently is hydrogen, a C 1-8 alkyl group, or a C 1-8 alkyl group having one to three halogen atoms;
  • R 4 is hydrogen, a C 1-8 alkyl group, a C 1-8 alkyl group having one to three halogen atoms, a three-membered to seven-membered cycloalkyl group, or a C 1-8 alkyl group having a three-membered to seven-membered cycloalkyl group;
  • each of P and Q independently is hydrogen, a halogen atom, a C 1-8 alkyl group, a C 1-8 alkyl group having one to three halogen atoms, nitro, cyano, hydroxyl, amino, a C 1-8 alkylamino group, a C 2-16 dialkylamino group, a C 2-8 acylamino group, a C 1-8 alkoxy group, a C 1-8 alkoxy group having one to three halogen atoms, or a heterocyclic group;
  • W is a C 1-8 alkyl group or a three-membered to seven-membered cycloalkyl group;
  • each of n and m independently is 1 or 2.
  • the invention further relates to an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome containing a compound having the following formula (VIII) or a pharmacologically acceptable salt thereof as an active ingredient:
  • R 2 is hydrogen, a C 1-8 alkyl group, a C 1-8 alkoxy group, a C 1-8 alkyl group having one to three halogen atoms, a C 1-8 alkoxy group having one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, a C 1-8 alkylamino group, a C 2-8 dialkylamino group, a C 2-8 acylamino group, a C 2-8 acylamino group having one to three halogen atoms, a C 1-8 alkylsulfonylamino group, carboxyl, a C 2-8 acyl group, an alkoxycarbonyl group comprising a C 1-8 alkoxy moiety, carbamoyl, a C 1-8 alkylthio group, a C 1-8 alkylsulfinyl group, a C 1-8 alkylsulfonyl group, or sulfamo
  • each of R 4 and R 5 independently is hydrogen, a C 1-8 alkyl group, or a C 1-8 alkyl group having one to three halogen atoms.
  • W is a five-membered or six-membered heterocyclic ring optionally having one or more substituents and comprising one to four nitrogen atoms as the members of the ring.
  • the invention further relates to an agent for preventing or treating neuropathic pain associated with Guillain-Barré syndrome containing 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)dione potassium salt as an active ingredient.
  • FIG. 3 shows influence of therapeutic administration of the compound A on pain threshold of EAN rat model.
  • the active ingredients of the agent of the invention for preventing or treating neuropathic pain associated with Guillain-Barré syndrome include the following compounds.
  • R 2 is hydrogen, chloro, bromo, nitro, cyano, —C(O)—OR 3 , or —C(O)—NR 4 R 5 , wherein each of R 2 , R 4 , and R 5 is hydrogen or a C 1-4 alkyl group; or in the alternative
  • R 1 is hydrogen
  • R 2 is chloro, bromo, nitro, cyano, —C(O)—OR 3 , or —C(O)—NR 4 R 5 , wherein each of R 3 , R 4 , and R 5 is hydrogen or a C 1-4 alkyl group.
  • R 1 is hydrogen
  • R 2 is chloro, bromo, nitro, or cyano.
  • R is a C 1-4 alkyl group, a C 2-4 alkynyl group, phenyl (optionally having one or more substituents selected from the group consisting of a lower alkyl group, an alkylthio group, an alkoxy group, a halogen atom, nitro, an acylamino group, methylsulfonyl, and methylenedioxy), or tetrahydronaphthyl;
  • R 1 is hydrogen
  • X is hydrogen, a C 1-4 alkyl group, a trifluoroalkyl group, hydroxyl, a halogen atom, methylthio, or an arylalkoxy group.
  • X is S or CH 2 ;
  • Y is O, S, or NH
  • each of R 2 and R 3 independently is hydrogen, a C 1-8 alkyl group, a C 1-8 alkoxy group, a C 1-8 alkyl group having one or more halogen atoms, a C 1-8 alkoxy group having one or more halogen atoms, a halogen atom, amino, carboxyl, hydroxyl, nitro, cyano, a C 2-8 acyl group, a C 6-10 aryl group, or a five-membered or six-membered heterocyclic group;
  • each of R 4 and R 5 independently is hydrogen, a C 1-8 alkyl group, or a C 1-8 alkyl group having one or more halogen atoms;
  • the double line consisting of a broken line and a solid line is a single bond or a double bond.
  • X a is O, S, or NH
  • R 1a is hydroxyl, tetrazolyl, N(R 5a )(R 6a ), a C 2-8 alkenyl group, a C 2-8 alkynyl group, a C 1-8 alkyl group having one or more halogen atoms, a C 1-8 alkoxy group having one or more halogen atoms, or a C 6-10 aryl group, wherein R 5a is hydrogen or a C 1-8 alkyl group, and R 6a is hydrogen, a C 1-8 alkyl group, or a C 2-8 acyl group;
  • each of R 2a and R 3a independently is hydrogen, a C 1-8 alkyl group, or a C 1-8 alkyl group having one or more halogen atoms;
  • R 4a is hydrogen, a C 1-8 alkyl group, a C 1-8 alkoxy group, a C 1-8 alkyl group having one or more halogen atoms, a halogen atom, hydroxyl, nitro, amino, carboxyl, tetrazolyl, cyano, a C 6-10 aryl group, or a five-membered or six-membered heterocyclic group.
  • X b is O, S, or NH
  • R 1b is a halogen atom, hydroxyl, tetrazolyl, N(R 5b )(R 6b ), a C 2-8 alkenyl group, a C 2-8 alkynyl group, a C 1-8 alkyl group having one or more halogen atoms, a C 1-8 alkoxy group having one or more halogen atoms, or a C 6-10 aryl group, wherein R 5b is hydrogen or a C 1-8 alkyl group, and R 6b is hydrogen, a C 1-8 alkyl group, or a C 2-8 acyl group;
  • each of R 2b and R 3b independently is hydrogen, a C 1-8 alkyl group, or a C 1-8 alkyl group having one or more halogen atoms;
  • R 4b is hydrogen, a C 1-8 alkyl group, an alkoxy group, a C 1-8 alkyl group having one or more halogen atoms, a halogen atom, hydroxyl, nitro, amino, carboxyl, tetrazolyl, cyano, a C 6-10 aryl group, or a five-membered or six-membered heterocyclic group; and
  • R 7b is a C 1-8 alkyl group.
  • X c is O, S, or NH
  • R 1c is hydrogen, a halogen atom, a C 1-8 alkyl group, a C 1-8 alkoxy group, hydroxyl, tetrazolyl, N(R 5c ) (R 6c ), a C 2-8 alkenyl group, a C 2-8 alkynyl group, a C 1-8 alkyl group having one or more halogen atoms, a C 1-8 alkoxy group having one or more halogen atoms, or a C 6-10 aryl group, wherein R 5c is hydrogen or a C 1-8 alkyl group, and R 6c is hydrogen, a C 1-8 alkyl group, or a C 2-8 acyl group;
  • each of R 2c and R 3c independently is hydrogen, a C 1-8 alkyl group, or a C 1-8 alkyl group having one or more halogen atoms;
  • R 4c is hydrogen, a C 1-8 alkyl group, an alkoxy group, a C 1-8 alkyl group having one or more halogen atoms, a halogen atom, hydroxyl, nitro, amino, carboxyl, tetrazolyl, cyano, a C 6-10 aryl group, or a five-membered or six-membered heterocyclic group;
  • R 7c is hydrogen or a C 1-8 alkyl group
  • R 8c is hydrogen, a C 1-8 alkyl group, or a C 2-8 acyl group.
  • X is O, S, or NH
  • Y is N or NR 6 , wherein R 6 is hydrogen or a C 1-8 alkyl group
  • R 1 is hydrogen, a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 1-8 alkyl group having one to three halogen atoms, or an alkyl group having phenyl;
  • R 2 is a C 1-8 alkyl group, a C 1-8 alkoxy group, a C 1-8 alkyl group having one to three halogen atoms, hydroxyl, nitro, amino, carboxyl, tetrazolyl, or cyano;
  • R 3 is hydrogen, a C 1-8 alkyl group, a C 1-8 alkoxy group, a C 1-8 alkyl group having one to three halogen atoms, a halogen atom, hydroxyl, nitro, amino, carboxyl, tetrazolyl, or cyano;
  • each of R 4 and R 5 independently is hydrogen, a C 1-8 alkyl group, or a C 1-8 alkyl group having one to three halogen atoms;
  • n 1 or 2;
  • the double line consisting of a solid line and a broken line is a double bond
  • the double line consisting of a solid line and a broken line is a single bond.
  • R 11 is hydrogen or a C 1-8 alkyl group
  • R 21 is a C 1-8 alkyl group, a C 1-8 alkoxy group, a C 1-8 alkyl group having one to three halogen atoms, or hydroxyl;
  • R 31 is hydrogen or a halogen atom.
  • A is an aryl group optionally having one or more substituents or a heterocyclic group optionally having one or more substituents;
  • B is an aryl group optionally having one or more substituents or a heterocyclic group optionally having one or more substituents;
  • X is a C 1-5 alkylene group or a bond
  • Y is a C 1-5 alkylene group optionally comprising a double bond
  • Z is O, S, N(R 5 ), or a bond, wherein R 5 is hydrogen or a C 1-8 alkyl group;
  • each of R 1 , R 2 , and R 3 independently is hydrogen, a C 1-8 alkyl group, or a C 1-8 alkyl group having one to three halogen atoms;
  • R 4 is hydrogen, a C 1-8 alkyl group, a C 1-8 alkyl group having one to three halogen atoms, a three-membered to seven-membered cycloalkyl group, or a C 1-8 alkyl group having a three-membered to seven-membered cycloalkyl group;
  • each of n and m independently is 1 or 2;
  • the substituent of the aryl group represented by A is not an alkyl group.
  • a 1 is phenyl or thienyl, each of which optionally has one to three substituents selected from the group consisting of a halogen atom, a C 1-8 alkyl group having one to three halogen atoms, nitro, cyano, hydroxyl, amino, a C 1-8 alkylamino group, a C 2-16 dialkylamino group, a C 2-8 acylamino group, a C 1-8 alkoxy group, a C 1-8 alkoxy group having one to three halogen atoms, an aryl group, and a heterocyclic group;
  • B 1 is an aryl group optionally having one or more substituents or a heterocyclic group optionally having one or more substituents;
  • Y 1 is a C 1-5 alkylene chain optionally comprising a double bond
  • Z 1 is O, S, N(R 7 ), or a bond, wherein R 7 is hydrogen or a C 1-8 alkyl group;
  • R 6 is hydrogen, a C 1-8 alkyl group, a C 1-8 alkyl group having one to three halogen atoms, or a three-membered to seven-membered cycloalkyl group.
  • a 2 is phenyl or thienyl, each of which optionally has one to three substituents selected from the group consisting of a halogen atom, a C 1-8 alkyl group having one to three halogen atoms, nitro, cyano, acetylamino, a C 1-8 alkoxy group, a C 1-8 alkoxy group having one to three halogen atoms, an aryl group, and a heterocyclic group;
  • B 2 is phenyl, naphthyl, benzofuranyl, 1,3-benzo[d]dioxolyl, quinolyl, indolyl, benzothienyl, thienyl, or pyridyl, each of which optionally has one to three substituents selected from the group consisting of a halogen atom, a C 1-8 alkyl group, a C 1-8 alkyl group having one to three halogen atoms, nitro, cyano, hydroxyl, amino, a C 2-8 acylamino group, a C 1-8 alkoxy group, a C 1-8 alkoxy group having one to three halogen atoms, a C 6-12 aryloxy group, sulfamoyl, a C 1-8 alkylsulfamoyl group, and a C 2-16 dialkylsulfamoyl group;
  • Z 2 is O, S, or NH
  • R 8 is hydrogen or a C 1-8 alkyl group.
  • B is an aryl group optionally having one or more substituents or a heterocyclic group optionally having one or more substituents;
  • Y is a C 1-5 alkylene group optionally comprising a double bond
  • Z is O, S, N(R 5 ), or a bond, wherein R 5 is hydrogen or a C 1-8 alkyl group;
  • each of R 1 , R 2 , and R 3 independently is hydrogen, a C 1-8 alkyl group, or a C 1-8 alkyl group having one to three halogen atoms;
  • R 4 is hydrogen, a C 1-8 alkyl group, a C 1-8 alkyl group having one to three halogen atoms, a three-membered to seven-membered cycloalkyl group, or a C 1-8 alkyl group having a three-membered to seven-membered cycloalkyl group;
  • each of P and Q independently is hydrogen, a halogen atom, a C 1-8 alkyl group, a C 1-8 alkyl group having one to three halogen atoms, nitro, cyano, hydroxyl, amino, a C 1-8 alkylamino group, a C 2-16 dialkylamino group, a C 2-8 acylamino group, a C 1-8 alkoxy group, a C 1-8 alkoxy group having one to three halogen atoms, or a heterocyclic group;
  • W is a C 1-8 alkyl group or a three-membered to seven-membered cycloalkyl group;
  • each of n and m independently is 1 or 2.
  • Y is methylene
  • Z is O or S
  • B is phenyl optionally having one to three substituents selected from the group consisting of a halogen atom, a C 1-8 alkyl group, a C 1-8 alkyl group having one to three halogen atoms, cyano, hydroxyl, a C 1-8 alkoxy group, a C 1-8 alkoxy group having one to three halogen atoms, benzyloxy, sulfamoyl, and a C 1-8 alkylsulfamoyl group.
  • R 1 is hydrogen, a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 1-8 alkyl group having one to three halogen atoms, or a C 1-3 alkyl group having phenyl;
  • R 2 is hydrogen, a C 1-8 alkyl group, a C 1-8 alkoxy group, a C 1-8 alkyl group having one to three halogen atoms, a C 1-8 alkoxy group having one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, a C 1-8 alkylamino group, a C 2-8 dialkylamino group, a C 2-8 acylamino group, a C 2-8 acylamino group having one to three halogen atoms, a C 1-8 alkylsulfonylamino group, carboxyl, a C 2-8 acyl group, an alkoxycarbonyl group comprising a C 1-8 alkoxy moiety, carbamoyl, a C 1-8 alkylthio group, a C 1-8 alkylsulfinyl group, a C 1-8 alkylsulfonyl group, or sulfamo
  • R 3 is hydrogen, a C 1-8 alkyl group, a C 1-8 alkoxy group, a C 1-8 alkyl group having one to three halogen atoms, a C 1-8 alkoxy group having one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, carboxyl, a C 2-8 acyl group, or an alkoxycarbonyl group comprising a C 1-8 alkoxy moiety; and
  • each of R 4 and R 5 independently is hydrogen, a C 1-8 alkyl group, or a C 1-8 alkyl group having one to three halogen atoms.
  • R 1 is hydrogen, a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 1-8 alkyl group having one to three halogen atoms, or a C 1-3 alkyl group having phenyl;
  • each of R 2 and R 3 independently is hydrogen, a C 1-8 alkyl group, a C 1-8 alkoxy group, a C 1-8 alkyl group having one to three halogen atoms, a C 1-8 alkoxy group having one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, a C 1-8 alkylamino group, a C 2-8 dialkylamino group, a C 2-8 acylamino group, a C 2-8 acylamino group having one to three halogen atoms, a C 1-8 alkylsulfonylamino group, carboxyl, a C 2-8 acyl group, an alkoxycarbonyl group comprising a C 1-8 alkoxy moiety, carbamoyl, a C 1-8 alkylthio group, a C 1-8 alkylsulfinyl group, a C 1-8 alkylsulfonyl group, or
  • each of R 4 and R 5 independently is hydrogen, a C 1-8 alkyl group, a C 1-8 alkyl group having one to three halogen atoms, or a C 1-3 alkyl group having phenyl;
  • W is a five-membered or six-membered heterocyclic ring optionally having one or more substituents and comprising one to four nitrogen atoms as the members of the ring.
  • the above-mentioned compounds can be prepared according to known processes.
  • the compounds described in (2) to (4) can be prepared according to a process described in WO 2004/085440.
  • the compounds described in (5) and (117) can be prepared according to a process described in Japanese Patent Publication No. 59(1984)-48826.
  • the compounds described in (8) to (16) can be prepared according to a process described in WO 2007/072974.
  • the compounds described in (17) to (36) can be prepared according to a process described in WO 2007/074970.
  • the compounds described in (37) to (52) can be prepared according to a process described in WO 2008/023847.
  • the compounds described in (53) to (79) can be prepared according to a process described in WO 2009/022730.
  • the compounds described in (80) to (94) can be prepared according to a process described in WO 2009/022731.
  • the compounds described in (95) to (102) can be prepared according to a process described in WO 2010/090300.
  • the compounds described in (103) to (116) can be prepared according to a process described in WO 2010/093061.
  • the compounds described in (7) and (117) such as paroxetine, imipramine are known compounds.
  • the chemical structures and the documents disclosing the processes for preparation of the compounds are described in The MERCK INDEX FOURTEENTH EDITION (2006) or the like. Further, these compounds are commercially available.
  • the selective serotonin reuptake inhibitors described in (6) include paroxetine, fluoxetine, fluvoxamine, and citalopram.
  • the pharmacologically acceptable salts in the active ingredients of the present invention include a salt with an acid (e.g., hydrochloric acid, acetic acid, benzoic acid, fumaric acid, besylic acid), an alkali metal (e.g., sodium, potassium, lithium), or an amine.
  • an acid e.g., hydrochloric acid, acetic acid, benzoic acid, fumaric acid, besylic acid
  • an alkali metal e.g., sodium, potassium, lithium
  • an amine e.g., sodium, potassium, lithium
  • the active ingredients of the present invention can be a geometrical (cis-trans) isomer or an optical isomer such as an optically active substance and racemic modification, each of which is included within the scope of the invention.
  • Hydrates can also be used as the active ingredients of the present invention.
  • Examples 3 and 4 as well as FIGS. 2 and 3 show analgesic activities of the compound A, which has P2X 4 receptor antagonism, on neuropathic pain originated from EAN.
  • P2X 4 receptor antagonist can be an effective therapeutic agent for the GBS neuropathic pain.
  • the preventive or therapeutic agent of the present invention can be administered to human beings by ordinary administration methods such as oral administration or parenteral administration.
  • the compound can be granulated in ordinary manners for the preparation of pharmaceuticals.
  • the compound can be processed to give tablets, granule, powder, capsule, suspension, injection, suppository, and the like.
  • Ordinary additives such as vehicles, disintegrators, binders, lubricants, and dyes are used for the preparation of these pharmaceuticals such as tablets.
  • vehicles lactose, D-mannitol, crystalline cellulose, and glucose can be mentioned.
  • starch and carboxymethylcellulose calcium (CMC-Ca) as the disintegrators, magnesium stearate and talc as the lubricants, and hydroxylpropylcellulose (HPC), gelatin and polyvinylpyrrolidone (PVP) as the binders.
  • the preparation of an injection can be made using solvents, stabilizers, dissolution-aids, suspensions, emulsifiers, soothing agents, buffers, or preservatives.
  • the compound of the invention can be administered to an adult generally in an amount of approximately 0.01 mg to 100 mg a day by parenteral administration and 1 mg to 2,000 mg a day by oral administration.
  • the dosage can be adjusted in consideration of age and conditions of the patient.
  • P2X 4 receptor antagonisms of the compound A (5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione potassium salt and paroxetine were measured as described below.
  • ATP receptors human P2X 4
  • 1321N1 cells were introduced into 1321N1 cells, and used as a stable ATP receptor-expressing system.
  • the obtained P2X 4 expressing 1321N1 cells were plated in a 96-well assay plate, and cultured 24 hours at 37° C. in an atmosphere of 5% CO 2 for calcium assay.
  • Fura-2 AM calcium fluorescent indicator was dissolved in an extracellular solution for calcium imaging.
  • the obtained solution was loaded onto the plated cells, and placed at room temperature for 45 minutes to introduce Fura-2 AM into the cells.
  • the fluorescence was detected by EnVision micro plate reader (PerkinElmer).
  • the cells were alternatively illuminated with two excitations wavelengths (lights through 340 nm and 380 nm filters) via xenon lamp, and the emitted fluorescence was measured at 510 nm.
  • the fluorescence changes were monitored to determine the fluorescence ratio (F340/F380) as the index of intracellular calcium change.
  • Measurements were conducted by adding 1 ⁇ M ATP to each well, and monitoring the ATP induced intracellular calcium responses with the passage of time. Tested compounds were treated to cells 15 min before the addition of ATP, and the inhibitory activities of compounds were calculated by comparing the calcium response with control in the absence of tested compound.
  • the P2 peptide-adjuvant solution was prepared by dissolving neuritogenic P2 peptide of peripheral myelin (amino acids 53-78: TESPFKNTEISFKLGQEFEETTADNR) in PBS, and mixing the obtained 2 mg/mL solution with complete Freund's adjuvant containing 2 mg/mL (the same concentration) of mycobacterium tuberculosis.
  • the spinal cord was collected after perfusion of 4% neutral buffered paraformaldehyde, embedded with paraffin to prepare slices.
  • a specimen in cross section was prepared at the fifth lumbar level (L5) of the spinal cord, and was subjected to an immunohistological staining using Iba1 antibody, which has widely been used as a microglia marker, and P2X 4 receptor antibody.
  • FIG. 1 The obtained immunostaining images are shown in FIG. 1 . It is observed that Iba1 (antigen specific to microglia)-positive cell signals (upper figures) and P2X 4 receptor-positive signals (lower figures) increase within L5 segment of the spinal cord, compared with the sides administered with only adjuvant.
  • FIG. 2 shows influence of preventive administration of the compound A on pain threshold of EAN rat model.
  • the animal was administered with P2 peptide, and neuritis associated with paresis of hind legs was observed about ten days after immunization. Further, allodynia was simultaneously observed. Thereafter, allodynia was continued for about 50 days.
  • the animal model was preventively administered with the compound A to suppress pains in initial and later manifestations of the disease.
  • FIG. 3 shows influence of therapeutic administration of the compound A on pain threshold of EAN rat model.

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WO2012161301A1 (fr) 2012-11-29
JPWO2012161301A1 (ja) 2014-07-31

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